title: Adenovirus-mediated intratumoral expression of immunostimulatory proteins in combination with systemic Treg inactivation induces tumor-destructive immune responses in mouse models.
abstract: Tumor-associated antigens (TAAs) include overexpressed self-antigens (for example, Her2/neu) and tumor virus antigens (for example, HPV-16 E6/E7). Although in cancer patients, TAA-specific CD4+ and CD8+ cells are often present, they are not able to control tumor growth. In recent studies, it became apparent that tumor site-located immune evasion mechanisms contribute to this phenomenon and that regulatory T cells have a major role. We tested in Her2/neu+ breast cancer and HPV-16 E6/E7+ cervical cancer mouse models, whether intratumoral expression of immunostimulatory proteins (ISPs), for example, recombinant antibodies (αCTLA-4, αCD137, αCD3), cyto/chemokines (IL-15, LIGHT, mda-7) and costimulatory ligands (CD80), through adenovirus(Ad)-mediated gene transfer would overcome resistance. In both the breast and cervical cancer model, none of the Ad.ISP vectors displayed a significant therapeutic effect when compared with an Ad vector that lacked a transgene (Ad.zero). However, the combination of Ad.ISP vectors with systemic T regulatory (Treg) depletion, using anti-CD25 mAb (breast cancer model) or low-dose cyclophosphamide (cervical cancer model) resulted in a significant delay of tumor growth in mice treated with Ad.αCTLA4. In the cervical cancer model, we also demonstrated the induction of a systemic antitumor immune response that was able to delay the growth of distant tumors. Ad.αCTLA4-mediated tumor-destructive immune responses involved NKT and CD8+ T cells. In both models no autoimmune reactions were observed. This study shows that Ad.αCTLA4 in combination with systemic Treg depletion has potentials in the immunotherapy of cancer.
authors.affiliation: Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.forename: S
authors.initials: S
authors.lastname: Tuve
authors.forename: J
authors.initials: J
authors.lastname: Persson
authors.forename: I
authors.initials: I
authors.lastname: Beyer
authors.forename: R
authors.initials: R
authors.lastname: Yumul
authors.forename: Z Y
authors.initials: ZY
authors.lastname: Li
authors.forename: K
authors.initials: K
authors.lastname: Tragoolpua
authors.forename: K-E
authors.initials: KE
authors.lastname: Hellström
authors.forename: S
authors.initials: S
authors.lastname: Roffler
authors.forename: A
authors.initials: A
authors.lastname: Lieber
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000276:Adjuvants, Immunologic / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines / Q000378:metabolism; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D019496:Cancer Vaccines; C556707:Ctla4 protein, mouse